RESUMEN
BACKGROUND: We aim to report two unrelated patients with pulmonary surfactant dysfunction (PSD) that carried two novel NKX2-1 frameshift variants, and evaluated the impact of these variants in vitro. METHODS: We enrolled children with PSD and NKX2-1 variants, and collected their clinical information and follow-up data. We constructed wild-type (WT) and variant NKX2-1 plasmids and transfected them into A549 and HEK293T cells. The functional characterization of variants was then evaluated by qRT-PCR, western blot, immunofluorescence, electrophoretic mobility shift assay, and dual-luciferase reporter assay. RESULTS: Two novel heterozygous frameshift variants of NKX2-1, i.e., c.705delC (Gly236Alafs*29) and c.313_316 dup (Asn106Lysfs*304), were identified in children from two unrelated families. We discerned attenuated mRNA and protein expression in the Asn106Lysfs*304 variant, and reduced DNA -binding as well as transcriptional activation capabilities in both variants. While the Asn106Lysfs*304 variant lost its synergistic interactions with PAX8 and TAZ, the Gly236Alafs*29 variant partially retained its residual transcriptional activation capabilities and synergistic interactions with PAX8 and TAZ. CONCLUSIONS: We reported on two children with two novel NKX2-1 frameshift variants. In vitro experiments revealed that the two frameshift variants have common and different mechanisms based on the loss or conservation of domains, which partially explained the phenotypical heterogeneity. IMPACT: Pulmonary surfactant dysfunction is a rare heterogeneous disease that exhibits a great burden on children's quality of life. We reported two novel NKX2-1 frameshift variants carried by two children with different clinical phenotypes, thus broadening our knowledge base of gene variations and phenotypes in NKX2-1. We performed an in vitro study and uncovered different pathogenic mechanisms underlying the actions of two novel variants, and thereby partially explained the mechanisms of phenotypical heterogeneity caused by NKX2-1 variants.
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Enfermedades Pulmonares Intersticiales , Calidad de Vida , Factores de Transcripción , Niño , Humanos , Mutación del Sistema de Lectura , Células HEK293 , Mutación , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Medical complexity of childhood interstitial lung disease (chILD) with connective tissue disease (CTD) poses a considerable challenge to pediatricians. METHODS: Clinical characteristics, laboratory findings, pulmonary function tests (PFTs), treatments and outcomes obtained for patients with CTD-chILD were analyzed in a prospective study. RESULTS: Patients' median age at diagnosis was 7 years old. About 29.4% (15/51) suffered rapidly progressive childhood ILD (RP-chILD) with a high mortality rate (33.3%, 5/15), and the incidence of RP-chILD in juvenile idiopathic inflammatory myopathies was as high as 41.6% and the mortality rate was 30% (3/10). More than 70% patients had decreased diffusion capacity. The mean interval from symptoms-onset to diagnosis was 11.3 months. Compared to chILD with known CTD, the chILD proceeded CTD had a longer diagnosis interval, higher mortality, hospital stays and costs (P < 0.05). Lung imaging (33.3%) and lung function (72.7%) were partially reversible. The average survival time was 68.6 months. Cox univariate analysis showed that HRCT score ≥3, experiencing RP-chILD, cyanosis, acute respiratory distress syndrome (ARDS) and CD4 T cell <200 were significant predictors of death for chILD, whereas Cox multivariate analysis showed that ARDS was significant predictor of death for CTD-chILD, while IVIG support combined with corticosteroids and immunosuppressants was a protective factor. CONCLUSIONS: Care providers should conduct an assessment for CTD in chILD as a longer interval between the diagnosis of chILD and the CTD is associated with increased mortality. Complications as ARDS predict poor outcome in CTD-chILD, while IVIG support combined with corticosteroids and immunosuppressants is a protective factor.
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Enfermedades del Tejido Conjuntivo , Enfermedades Pulmonares Intersticiales , Síndrome de Dificultad Respiratoria , Humanos , Niño , Estudios Prospectivos , Inmunoglobulinas Intravenosas , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades del Tejido Conjuntivo/complicaciones , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/epidemiología , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéuticoRESUMEN
BACKGROUND: Clinically amyopathic juvenile dermatomyositis (CAJDM) is a clinical subgroup of juvenile dermatomyositis (JDM), characterized by JDM rashes with little or no clinically evident muscle weakness. Interstitial lung disease (ILD) is an uncommon but potentially fatal complication of juvenile dermatomyositis (JDM). While adults with dermatomyositis-associated ILD usually present respiratory symptoms before or at the same time as skin muscle manifestations, only a few studies have covered the onset of respiratory symptoms of ILD in JDM patients, especially CAJDM. There is currently no clear effective treatment regime or any prognostic factors for CAJDM-associated ILD. CASE PRESENTATION: Here, we report the first case of a CAJDM patient who presented with respiratory symptoms as the initial manifestation. A 10-year-old male patient presented to the hospital with a complaint of progressive cough and chest pain. Violaceous macule and papules appeared a few days later and he was positive for anti-Ro-52 antibodies. Imaging showed diffuse interstitial infiltration in both lungs and lung function tests showed restrictive and obstructive ventilatory dysfunction. Muscular abnormalities were excluded by thigh magnetic resonance imaging (MRI) and electromyography. Skin biopsy showed pathognomonic findings consistent with DM. Lung biopsy indicated chronic inflammation of the mucosa. This patient was finally diagnosed with CAJDM complicated by ILD and prescribed methylprednisolone, immunoglobulin, prednisolone and mycophenolate mofetil (MMF) for treatment. The patient's cutaneous and respiratory manifestations were largely improved. We retrospectively reviewed this and another six cases with CAJDM-associated ILD reported previously to better understand its clinical characteristics and effective management. CONCLUSIONS: Initial respiratory symptoms with rapid progression in patients presenting Gottron papules should be considered manifestations of CAJDM-associated ILD. We also found a combination of corticosteroids, IVIG and MMF to be an effective method of arresting the progress of CAJDM-associated ILD and improving the prognosis of the patients.
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Dermatomiositis , Enfermedades Pulmonares Intersticiales , Adulto , Niño , Dermatomiositis/complicaciones , Dermatomiositis/diagnóstico , Humanos , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Masculino , Estudios Retrospectivos , PielRESUMEN
We present a case report that entails prenatal ultrasonography, postnatal characteristics, and molecular genetic analysis of a newborn who presented with thanatophoric dysplasia type I (TDI) with a mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A malformed newborn with tachypnea, delivered by caesarean at the gestational age of 39â¯weeks, was the first child of nonconsanguineous parents by a spontaneous pregnancy. Features in prenatal ultrasonography and postnatal radiography were consistent with the diagnosis of TDI, presenting with short body length (38â¯cm, <3rd percentile), redundant skin folds, a narrow thorax with a bust of 29.5â¯cm (3-5th percentile), and macrocephaly with a head circumference of 36â¯cm (>97th percentile). The proposita had postnatal dyspnea and unfortunately died of respiratory failure at the age of 13â¯days. Molecular genetic analysis revealed a mutation of c.2419â¯Tâ¯>â¯C (p. Ter807Arg) (X807R) in FGFR3. Live-born infants with TDI are exceedingly rare, and we hereby report a newborn with a c.2419â¯Tâ¯>â¯C mutation in FGFR3, emphasizing phenotype with clinical characteristics and ultrasonographic and X-ray findings, to raise awareness about the heterogeneous patterns of TD.
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Mutación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/deficiencia , Displasia Tanatofórica/genética , Displasia Tanatofórica/patología , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Femenino , Edad Gestacional , Humanos , Recién Nacido , Fenotipo , Embarazo , Pronóstico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
BACKGROUND: Mutations in the surfactant protein C gene (SFTPC) result in interstitial lung disease (ILD). Our objective was to characterize clinical and genetic spectrum of ILD in Chinese children associated with SFTPC mutations. METHODS: Six Chinese children with ILD heterozygous for SFTPC mutations were included. Candidate genes responsible for surfactant dysfunction were sequenced by next-generation sequencing. Subclones of SFTPC with novel mutations were generated and transiently transfected into A549 cells. The functional characterization of mutant surfactant protein C (SP-C) was evaluated by Western blotting and immunofluorescence. RESULTS: The age of onset ranged from 7 days to 15 months. All cases required supplemental oxygen. Failure to thrive (5/6) was the most significant extra-pulmonary manifestation. Hydroxychloroquine was given as the long-term treatment of lung disease in four patients and two of them responded well. Three mutations were identified in six patients: four with I73T, one with D105G, one with Y113H. Mutations in three patients were inherited and three arised de novo. Western blotting revealed totally different band patterns between mutant SP-C (D105G and Y113H) and the wildtype. Immunofluorescence showed mutant SP-C (D105G) was scarcely trafficked to lamellar bodies but localized well to early endosomes, which was in marked contrast to the wildtype protein. CONCLUSION: SFTPC mutations were an important cause of childhood ILD in Chinese population. I73T was a common SFTPC mutation in Chinese ILD children associated with surfactant protein C mutations.
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Pueblo Asiatico/genética , Enfermedades Pulmonares Intersticiales/genética , Mutación/genética , Proteína C Asociada a Surfactante Pulmonar/genética , China , Estudios de Cohortes , Femenino , Humanos , Lactante , Recién Nacido , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/terapia , MasculinoRESUMEN
BACKGROUND AND OBJECTIVE: Population-specific pulmonary function reference data are essential to identify the nature and severity of respiratory diseases. However, there is a lack of reference data for Chinese neonates and infants. The objective of this study was to develop reference data for tidal breathing and plethysmographic measurements for Chinese subjects during the first 2 years of life. METHODS: Data of tidal breathing and plethysmography from healthy Chinese neonates (≤28 days) and infants (1-24 months) using the Jaeger MasterScreen BabyBody were collated. All subjects were sedated for the tests. Multivariable analyses were performed to determine predictive variables for the pulmonary function parameters. Reference equations for outcomes were constructed using multilevel modelling and the LMS (lambda-mu-sigma) method was used for establishing smoothed reference percentiles. RESULTS: Four hundred and ten healthy subjects were tested. Acceptable measurements of tidal breathing analysis and plethysmography outcomes were obtained in 396 (96.6%) and 370 (90.4%) subjects, respectively. Normal reference percentiles and equations for the main parameters of tidal breathing and plethysmography were derived from test occasions of 211 neonates and 185 infants. Body weight, crown-heel length and age were significantly associated with lung function, of which length was the strongest predictor. CONCLUSION: This study provides reference data of BabyBody-plethysmographic measurements for healthy Chinese subjects in their first 2 years of life. Weight and length are the strongest predictors for neonatal and infant lung function, respectively.
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Pulmón , Pletismografía , Respiración , Enfermedades Respiratorias/diagnóstico , Pueblo Asiatico/estadística & datos numéricos , Tamaño Corporal , China , Femenino , Humanos , Lactante , Recién Nacido , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Pletismografía/métodos , Pletismografía/normas , Valores de Referencia , Reproducibilidad de los Resultados , Pruebas de Función Respiratoria/métodosRESUMEN
BACKGROUND: Wheezing is common in early childhood and remains an important health concern. The aim of this study was to assess the lung function of wheezing infants and to investigate the relationship between lung function and respiratory outcome. METHODS: Infants <2 years of age with acute lower respiratory tract infection (ALRTI) who had undergone lung function tests were included in the study. They were assigned to wheeze or no wheeze group based on physical examination. Infants without any respiratory diseases were enrolled as controls. Lung function was measured during the acute phase and 3 months after ALRTI. One-year follow-up for infants with ALRTI was achieved. RESULTS: A total of 252 infants with ALRTI who had acceptable data regarding tidal breathing were included in the final analysis. Compared with the control and the no wheeze groups, infants in the wheeze group had significantly decreased time to peak tidal expiratory flow as a percentage of total expiratory time (TPTEF/TE) (20.1 ± 6.4% vs. 34.4 ± 6.2% and 26.4 ± 8.3%, respectively, P < 0.0001) and significantly increased peak tidal expiratory flow (PTEF) (90.7 ± 26.3 ml/s vs. 79.3 ± 18.4 ml/s and 86.1 ± 28.0 ml/s, respectively, P < 0.01), sReff and Reff. The infants in the wheeze group still had lower TPTEF/TE and volume to peak tidal expiratory flow as a percentage of total expiratory volume (VPTEF/VE) than the no wheeze infants 3 months after the ALRTI. Moreover, there was a significant inverse relationship between TPTEF/TE, VPTEF/VE, and the recurrence of wheezing and pneumonia. CONCLUSIONS: Impaired lung function was present in wheezing infants with ALRTI and the deficits persisted. In addition, the lower level of TPTEF/TE and VPTEF/VE was a risk factor for poor respiratory outcome.
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Pulmón/fisiología , Ruidos Respiratorios/fisiología , Infecciones del Sistema Respiratorio/fisiopatología , Femenino , Humanos , Lactante , Recién Nacido , Pulmón/patología , Masculino , Neumonía/etiología , Neumonía/fisiopatología , Pruebas de Función Respiratoria , Infecciones del Sistema Respiratorio/complicaciones , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
BACKGROUND: To investigate the clinical characteristics and analyze risk factors for severe respiratory syncytial virus (RSV) infection in hospitalized infants with acute lower respiratory tract infections (ALRIs). METHODS: A retrospective review of the medical records of infants with RSV-associated ALRIs between March 1st, 2011 and February 29th, 2012 was conducted. Subjects were followed up over the phone or by outpatient visit six and twelve months after discharge. RESULTS: Among 913 RSV-associated ALRIs infants, 288 (31.5%) had severe infections, which accounted for 4.2% of hospitalized children. The hospital RSV mortality rate was 1.0%. The proportions of cases with tachypnea, apnea, cyanosis, and fine rales were significantly higher in the severe ALRIs group (all P<0.001). Multivariate logistic regression showed that low-birth-weight [1.698 (1.028-2.805)], age less than 3 months old [3.385 (2.174-5.271)], congenital heart disease [1.667 (1.149-2.418)], bronchopulmonary dysplasia [8.505 (1.731-41.780)], and airway abnormalities [2.246 (1.008-5.005)] were independent risk factors for severe ALRIs. The incidence of bronchitis, pneumonia and readmission in the severe group was significantly higher than that of the non-severe group during the one-year follow-up (all P<0.001). CONCLUSIONS: Younger age, low birth weight and underlying disease are associated with severe RSVassociated ALRIs. Furthermore, severe RSV infections may be associated with a higher frequency of subsequent bronchitis, pneumonia and re-hospitalization in the following year.
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Infecciones por Virus Sincitial Respiratorio/epidemiología , Enfermedad Aguda , Niño Hospitalizado , China/epidemiología , Femenino , Humanos , Lactante , Masculino , Reacción en Cadena de la Polimerasa/métodos , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Body plethysmography is a typical method to measure functional residual capacity (FRC) and airway resistance (Raw). The aim of the study was to test the feasibility of measuring lung function with the body plethysmography in young children with acute lower respiratory tract infection (ALRI) by evaluating changes and prognosis of lung function for infants with ALRI with or without wheezing via body plethysmograph. METHOD: Pulmonary function tests (PFTs) were performed by using body plethysmography in 444 children with ALRI, aged 1-36 months, to assess their tidal breathing parameters such as ratio of time to peak tidal expiratory flow to total expiratory time (TPTEF/TE), ratio of volume to peak tidal expiratory flow to total expiratory volume (VPTEF/VE), plethysmographic functional residual capacity (FRCP), FRCP per kilogram (FRCP/kg), specific effective airway resistance (sReff), effective airway resistance (Reff), Reff per kilogram (Reff/kg), etc. According to whether there was wheezing or not, children who had ALRI with wheezing were classified as Group-W, or without wheezing as Group-N. Changes or correlations of tidal breathing parameters and plethysmographic parameters were compared.One hundred and three contemporaneous healthy controls aged 1-36 months underwent the same tests for comparison. And 36 wheezing children accepted PFTs at follow-up in recovery phase. RESULT: Mean values of TPTEF/TE in Group-W,Group-N and the Control respectively were (20.5 ± 6.7)%,(22.8 ± 6.5)%,(34.6 ± 5.0)% (F = 110.500, P < 0.001), while VPTEF/VE respectively were (23.0 ± 6.3)%,(25.2 ± 6.8)%,(34.5 ± 4.2)% (F = 107.800, P < 0.001). Compared to the Control,Group-W and Group-N had significantly higher values of FRCP (226 vs. 176 vs. 172 ml, χ(2) = 64.870, P < 0.001), FRCP/kg(24.40 vs.17.80 vs.17.60 ml/kg,χ(2) = 68.890, P < 0.001), sReff(1.00 vs. 0.52 vs. 0.46 kPa·s,χ(2) = 75.240, P < 0.001), Reff (3.90 vs.2.74 vs.2.20 kPa·s/L, χ(2) = 36.480, P < 0.001) and Reff/kg [0.42 vs. 0.29 vs.0.22 kPa·s/(L·kg), χ(2) = 29.460, P < 0.001]. Although 25 (12.8%) wheezing children with ALRI had normal values of tidal breathing parameters, they already had increased FRCP, FRCP /kg, sReff, Reff and Reff/kg (t = 2.221, 1.997, 2.502, 2.587, 2.539, all P < 0.05). Values of FRCP and Reff in infants caught ALRI were inversely correlated to that of TPTEF/TE and VPTEF/VE (P < 0.05); 36 children with wheezing who accepted PFTs at follow-up had shown significant decline in the specific parameters of plethysmography such as FRCP, FRCP/kg, sReff, Reff and Reff/kg (Z = -1.999, -2.195, -2.038, -1.823, -2.054, all P < 0.05), while no improvement in the main parameters of tidal breathing such as TPTEF/TE. CONCLUSION: Measuring lung function with the body plethysmography in young children with ALRI is feasible. FRC and Raw, as special lung function testing parameters of body plethysmography, were sensitive indicators reflecting impairment of lung function in infants with ALRI (especially for children caught ALRI with wheezing) and shows significant correlation with parameters from lung function testing via tidal breathing. Therefore plethysmography is worthy of clinical promotion.
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Resistencia de las Vías Respiratorias/fisiología , Capacidad Residual Funcional/fisiología , Pulmón/fisiopatología , Pletismografía Total , Enfermedades Respiratorias/fisiopatología , Estudios de Casos y Controles , Preescolar , Femenino , Humanos , Lactante , Masculino , Pruebas de Función Respiratoria , Ruidos Respiratorios/diagnóstico , Ruidos Respiratorios/fisiopatología , Enfermedades Respiratorias/diagnóstico , Volumen de Ventilación PulmonarRESUMEN
OBJECTIVE: To investigate the clinical epidemiologic characteristics and analyze risk factors for acute respiratory syncytial virus (RSV) infection in hospitalized infants with acute lower respiratory tract infection (ALRI). METHOD: ALRI infants admitted to Children's Hospital of Fudan University from March 1st, 2011 to February 29th, 2012, were enrolled in this study. Patient information included demographic characteristics, feeding history, family status, clinical presentation, accessory examination, treatment and prognosis. According to the etiology of ALRI infants, we compared the seasonal distribution, demographic characteristics, household characteristics and underlying diseases between RSV-positive patients and RSV-negative patients. Univariate and multiple Logistic regression analyses were used to determine factors that were associated with risk of RSV infection. RESULT: Among 1 726 ALRI infants, there were 913 RSV-positive infants (52.9%). The occurrence of RSV infection had a seasonal variation, with a peak in winter (59.1%). The median (P25, P75) age of RSV infants was 64 (21-155) days. The gestational age (GA) and body weight (BW) was (37.5 ± 2.4) weeks and (3.07 ± 0.66) kg, respectively. The male/female ratio among these was 1.9: 1. RSV infection was more popular among infants in the families with smoking members, crowded living conditions, history of atopic mother. Differences of the proportion of patients with underlying disease between RSV-positive and negative groups were statistically significant (59.4% vs. 54.2%, P < 0.05). Univariate logistic regression demonstrated that factors increasing the risk of RSV infection were: GA<37 weeks (OR = 1.346, 95%CI: 1.037-1.748), birth weight <2 500 g (OR = 1.447, 95%CI: 1.103-1.898), underlying diseases (OR = 1.232, 95%CI: 1.018-1.492), underlying CHD (OR = 1.391, 95%CI: 1.120-1.728), environmental tobacco smoke exposure (OR = 1.254, 95%CI: 1.035-1.519), mother with atopic diseases (OR = 1.827, 95%CI: 1.296-2.573), crowded house with four or more than four family members (OR = 1.232, 95%CI: 1.013-1.498), autumn or winter infection (OR = 1.351, 95%CI: 1.024-1.783; OR = 1.713, 95%CI: 1.332-2.204). Multivariate logistic regression determined the factors increasing the risk of RSV infection were: underlying CHD (OR = 1.298, 95%CI: 1.002-1.681), mother with atopic diseases (OR = 1.766, 95%CI: 1.237-2.520), autumn or winter infection (OR = 1.481, 95%CI: 1.105-1.985; OR = 1.766, 95%CI: 1.358-2.296). CONCLUSION: The prevalence of RSV infection was the highest in winter, while preterm and low birth weight infants were more susceptible. Underlying diseases were found in 59.4% cases, CHD was the most common one. The factors increasing the risk of RSV infection were: CHD, mother with atopic diseases, autumn or winter infections.